DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

ergot alkaloids are used primarily to prevent postpartum hemorrhage.
Although all natural ergot alkaloids have qualitatively the
same effect on the uterus, ergonovine is the most active and also is
less toxic than ergotamine. For these reasons ergonovine (ERGO-
TRATE) and its semisynthetic derivative methylergonovine
(METHERGINE, others) have replaced other ergot preparations as
uterine-stimulating agents in obstetrics.
Methysergide. Methysergide (SANSERT; 1-methyl-d-lysergic acid
butanolamide) is a congener of methylergonovine (Table 13–6).
Reflecting the fickle nature of the ergot compounds, methysergide is
neither a selective antagonist nor always an antagonist. It interacts
with 5-HT 1
receptors, but its therapeutic effects appear primarily to
reflect blockade of 5-HT 2
receptors; it blocks 5-HT 2A
and 5-HT 2C
receptors, but has partial agonist activity in some preparations.
Although methysergide is an ergot derivative, it has only weak vasoconstrictor
and oxytocic activity.
Methysergide is without benefit when given during an acute
migraine attack but has been used for the prophylactic treatment of
migraine and other vascular headaches, including Horton’s syndrome.
A potentially serious complication of prolonged treatment is
inflammatory fibrosis, giving rise to various syndromes that include
retroperitoneal fibrosis, pleuropulmonary fibrosis, and coronary and
endocardial fibrosis. Usually the fibrosis regresses after drug withdrawal,
although persistent cardiac valvular damage has been
reported. Because of this danger, other drugs are preferred for the
prophylactic treatment of migraine (see the earlier discussion of
migraine therapy). If methysergide is used chronically, treatment
should be interrupted for 3 weeks or more every 6 months.
Methysergide is not available in the U.S.
D-Lysergic Acid Diethylamide (LSD). Of the many drugs that are nonselective
5-HT agonists, LSD (see structure in Table 13–6) is the
most remarkable. This ergot derivative profoundly alters human
behavior, eliciting perception disturbances such as sensory distortion
(especially visual) and hallucinations at doses as low as 1 μg/kg.
The potent, mind-altering effects of LSD explain its abuse by
humans (Chapter 24), as well as the fascination of scientists with the
mechanism of action of LSD.
LSD was synthesized in 1943 by Albert Hoffman, who discovered
its unique properties by accidental ingestion of the drug.
The chemical precursor, lysergic acid, occurs naturally in a fungus
that grows on wheat and rye but is devoid of hallucinogenic actions.
LSD contains an indolealkylamine moiety embedded within its
structure, and early investigators postulated that it would interact
with 5-HT receptors. Indeed, LSD interacts with brain 5-HT receptors
as an agonist/partial agonist. LSD mimics 5-HT at 5-HT 1A
autoreceptors on raphe cell bodies, producing a marked slowing of
the firing rate of serotonergic neurons. In the raphe, LSD and 5-HT
are equi-effective; however, in areas of serotonergic axonal projections
(such as visual relay centers), LSD is far less effective than is
5-HT. In an animal behavioral model thought to reflect the subjective
effects of abused drugs, the discriminative stimulus effects of
LSD and other hallucinogenic drugs appear to be mediated by activation
of 5-HT 2A
receptors (Winter, 2009). Recent studies of 5-HT 2A
receptor knockout mice confirm the critical role for this receptor in
LSD hallucinogenic effects (González-Maeso et al., 2007). LSD also
interacts potently with many other 5-HT receptors, including cloned
receptors whose functions have not yet been determined. On the
other hand, the hallucinogenic phenethylamine derivatives such as
1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane are selective
5-HT 2A/2C
receptor agonists. Current theories of the mechanism of
action of LSD and other hallucinogens focus on 5-HT 2A
receptormediated
disruption of thalamic gating with sensory overload of the
cortex (Geyer and Vollenweider, 2008). Progress in understanding
the unusual properties of hallucinogens are arising from clinical
investigations. For example, positron emission tomography imaging
studies revealed that administration of the hallucinogen psilocybin
(the active component of “shrooms”) mimics the pattern of brain
activation found in schizophrenic patients experiencing hallucinations.
Consistent with animal studies, this action of psilocybin is
blocked by pretreatment with a 5-HT 2A/2C
antagonist.
8-Hydroxy-(2-N,N-Dipropylamino)-Tetraline (8-OH-DPAT). This prototypic
5-HT 1A
-selective receptor agonist is a valuable experimental tool.
HO
N(CH 2 CH 2 CH 3 ) 2
8-OH-DPAT
8-OH-DPAT is considered to be a 5-HT 1A
selective agonist.
It does not interact with other members of the 5-HT 1
-receptor subfamily
or with 5-HT 2
, 5-HT 3
, or 5-HT 4
receptors, although activation
of the 5-HT 7
receptor has been reported. 8-OHDPAT reduces the firing
rate of raphe cells by activating 5-HT 1A
autoreceptors and
inhibits neuronal firing in terminal fields (e.g., hippocampus) by
direct interaction with postsynaptic 5-HT 1A
receptors.
Buspirone (BUSPAR, others). A series of long-chain arylpiperazines,
such as buspirone, gepirone, and ipsapirone, are selective partial agonists
at 5-HT 1A
receptors. Other closely related arylpiperazines act
as 5-HT 1A
-receptor antagonists. Buspirone, the first clinically available
drug in this series, has been effective in the treatment of anxiety
(Chapter 15). Buspirone mimics the antianxiety properties of
benzodiazepines but does not interact with GABA A
receptors and or
display the sedative and anticonvulsant properties of benzodiazpeines.
The absence of sedative effects may explain why patients
prefer the benzodiazepines to relieve anxiety.
m-Chlorophenylpiperazine (mCPP). The actions of mCPP in vivo primarily
reflect activation of 5-HT 1B
and/or 5-HT 2A/2C
receptors,
although this agent is not subtype selective in radioligand-binding
studies in vitro.
H
N
N
mCPP
CI
349
CHAPTER 13
5-HYDROXYTRYPTAMINE (SEROTONIN) AND DOPAMINE